Patients suffering from Alzheimer's disease show significantly decreased levels of cholinergic neurons and acetylcholine secretion in most of the cerebral cortex. Therefore, it has been known that cognitive impairment in the patients can be ameliorated by increasing the cerebral acetylcholine level. Acetylcholinesterase inhibitors inhibit the acetylcholinesterase (AChE) to increase the cerebral acetylcholine level, thereby being used for the management of Alzheimer's disease symptoms. Currently developed acetylcholinesterase inhibitors include tacrine (1993), donepezil (1996), rivastigmine (1999) and galantamine (2001), which were approved by the U.S. Food and Drug Administration (FDA) for treating Alzheimer's disease. For example, Aricept™ (Eisai), donepezil-containing tablet, is an oral formulation which is administered once daily at bedtime.
Meanwhile, it has been known that oral administration of the donepezil-containing tablet causes gastrointestinal side effects such as diarrhea, vomiting, loss of appetite, and muscle cramps. And also, the patients suffering from Alzheimer's disease should repeatedly take the drug once every day (at bedtime), which results in lowering patients' compliance, thereby making it difficult to maintain the pharmacological effect thereof continuously. Therefore, a donepezil-containing transdermal delivery system is expected to avoid the gastrointestinal side effects according to oral administration and improve patients' compliance. Especially, a transdermal delivery system is expected to continuously maintain the desired pharmacological effect, through releasing the drug substance in continuous manner for a long period of time.
There have been disclosed various transdermal delivery systems comprising donepezil or its salt. For example, transdermal delivery systems comprising donepezil or its salt have been disclosed in various prior arts including U.S. Pat. No. 6,815,454, US Patent Publication No. 2009/0175929, US Patent Publication No. 2010/0080842, US Patent Publication No. 2012/0207816, WO 2003/032960, Korean Patent Publication No. 10-2009-0101667, Korean Patent Publication No. 10-2011-0030349, Korean Patent Publication No. 10-2011-0109995, etc.
However, most of the transdermal delivery systems disclosed in prior arts involve the use of various permeation enhancers in a large amount in order to overcome the low skin permeation rate of drug substance, which causes adverse events such as rashes or skin irritation.
And also, it is difficult to maintain skin permeation rate in a desired level for a long period of time (e.g., for 7 days or more), which is necessary for improving patients' compliance. For example, in case of the transdermal delivery system disclosed in WO2003/032960, the skin permeation rate reaches maximum level of 2˜2.5 μg/cm2/hr and then decreased rapidly. At 48 hours after applying the transdermal delivery system, the skin permeation rate thereof is decreased to about 1 μg/cm2/hr, which makes it difficult to maintain the therapeutic effect continuously. And also, there have been disclosed transdermal delivery systems wherein a release-controlling layer is inserted between two or more drug-containing layers (e.g., Korean Patent Publication No. 10-2011-0030349, EP 2,399,607, etc.). However, the transdermal delivery systems having a multi-layer structure have problems such as complicated manufacturing processes in industrial mass production; and high production cost.
In addition, crystallization of drug substance in a transdermal delivery system causes various problems, such as decrease in adhesive force, variation in skin permeation rate, storage problems, etc., which make it difficult to incorporate drug substance in a high concentration into a transdermal delivery system. US Patent Publication Nos. 2010/0080842 and 2009/0175929 have disclosed a transdermal delivery systems obtained by using an acrylic pressure-sensitive adhesive having carboxylic acid functionalities or hydroxyl functionalities, as well as using a specific permeation enhancer or a specific crystal form of donepezil (type-B crystal polymorphism) or a specific crystallization-inhibiting agent (i.e., a (meth)acrylate copolymer having a carboxylic group). However, if an acrylic pressure-sensitive adhesive is used as a matrix of the transdermal delivery system, the drug diffusion is slowed in the pressure-sensitive adhesive layer due to the interaction between donepezil and the acrylic polymer in the layer, which also reduces movement of the drug from the pressure-sensitive adhesive layer to the skin. In order to solve this problem, Korean Patent Publication No. 10-2009-0101667 has disclosed a transdermal delivery system obtained by using an EVA (ethylene vinyl acetate) adhesive and a rosin ester resin as a crystallization-inhibiting agent.
Therefore, there is a need to develop a transdermal delivery system which can solve said problems, such as adverse events (e.g., rashes or skin irritation); difficulties in maintaining the skin permeation rate for a long period of time (e.g. for 7 days or more); complicated manufacturing processes and high production cost associated with forming a release-controlling layer additionally; and problems originated from crystallization in the matrix (e.g., decrease in adhesive force, variation in skin permeation rate, and difficulty in incorporating drug substance in a high concentration, etc.). Especially, in designing a transdermal delivery system used for a long period of time such as 7 days or more, selection of the optimum adhesive is very critical for both minimizing potential variation in skin permeation rate and avoiding any potential crystallization, which are originated from interaction between drug substance and an adhesive. And also, there is a need to develop a transdermal delivery system comprising a drug-containing matrix layer having a single-layer structure that is easily applicable to industrial mass production, the transdermal delivery system of which can release a drug continuously, thereby achieving the therapeutic effects for a long period of time (for 7 days or more) even when applied only once; requires using a permeation enhancer in a small amount; and has excellent physicochemical stability. In addition, other problems, such as air bubble formation in the formulation and deformation after applying the formulation to the skin, should be also solved to achieve consistency and/or continuity in skin permeation rate of drug substance.